Messenger RNA Degradation: A Story of Translational Flux
Messenger RNA Degradation within Translation Control and in the Big Picture of Gene Regulation: ]] As shown in figure 1, there are several regulated steps of mRNA regulation beginning with transcription control of the DNA template. Not shown, are the levels of regulation prior to transcriptional regulation, including epigenetic modifications. Once the mRNA transcript is made, regulated by transcriptional control, there are various degrees of RNA processing controls (including alternative splicing and the 5-prime 7-methylguanylate cap and 3-prime poly-adenine tail), RNA transport controls, and finally, translation controls. In Eukaryote cells, once the mRNAs are in the cytoplasmic, the major regulatory control is the stability of the mRNA transcriptMechanisms governing the control of mRNA translation Mark Livingstone et al 2010 Phys. Biol. 7''' 021001 http://www.ncbi.nlm.nih.gov/pubmed/20463379 . '''How many elements control mRNA stability? An mRNA must be stable in order to be translated by the ribosomes complex. If an mRNA is destroyed, than it cannot be translated.There are several features of cytoplasmic mRNAs that influence the stability of each transcript, often by stabilizing proteins. 5-Prime untranslated regions (UTRs): ''These include Internal Ribosome Entry Sites( IRES), Up-stream opening reading frames, terminal oligoprymidine sequences (TOPS), and secondary structures. Scanning enzymes for both mRNA translation and degradation bind to the TOPS cap. The regulatory effect of TOPS on mRNA degradation is diminished when there is a long 5-prime UTR. The mRNA regulatory elements contained within the 5-prime untranslated region There are many contributions from regulatory elements in the 5-prime UTR. In order to understand the complexity, researchers have divided mRNAs into 3 classes of 5-prime UTRs. C''lass I includes poorly translated mRNAs that have long 5’-UTRs with elements that inhibit translation. Class II includes TOPs mRNAs that are regulated via growth-dependent signalling. Class III includes mRNAs with elements in the 5’-UTR promote efficient translationKnapinska, Anna M. 2003, Molecular Mechanisms Regulating mRNA Stability: Physiological and Pathological Significance, Current Genomics, http://rci.rutgers.edu/~yannis/publications/Brewer-MS.pdf. Coding Region: ''Some sequences are associated with increased or decreased stability, but not all mRNAs' stability is determined by coding sequences. This is difficult to study, because by adding or removing sequences, the influence on mRNA size can confound the results, as opposed to the influence of the specific sequence. ''3-Prime UTRs: The best characterized elements are Adeneine (A) and Uracil (U) rich elements. In general, high AU repeats are associated with increased mRNA stability and decreased translational efficiency. Again, there are many examples of AU rich elements, which have been divided into 3 classes: Class I AU rich elements are repeats of AUUUA. C''lass II'' contains AU regions with the AUUUA sequence interspersed throughout. Class III ''are AU rich elements with more U's than A's. The degradation of mRNA by these sequences generally follows a process where specific proteins bind to the AU rich sequences, resulting in removal of the poly-A tail and rapid degradation. There are often several proteins which recognize a specific sequence, which themselves are regulated by upstream pathways Knapinska, Anna M. 2003, Molecular Mechanisms Regulating mRNA Stability: Physiological and Pathological Significance, Current Genomics, http://rci.rutgers.edu/~yannis/publications/Brewer-MS.pdfRoss J., 1995, mRNA stability in mammalian cells, Microbiol Review, http://www.ncbi.nlm.nih.gov/pubmed/7565413. ''The poly-Adenine tail: This feature seems to be a general protection again indiscriminate degradation of cytoplasmic mRNAs. This is determined by observing rapid destruction of mRNAs lacking a poly-A tail. protein, aptly named Poly-A Binding Protein (PABP), binds to the poly-A tail and protects the mRNAs from degradationRoss J., 1995, mRNA stability in mammalian cells, Microbiol Review, http://www.ncbi.nlm.nih.gov/pubmed/7565413 . Regulation of Stem loop instability: Based on secondary structures, many mRNAs that code for acute phase proteins involved in cell cycle, growth, and metabolism are predicted to be highly unstable. When their protein product is no longer needed, this instability confers their rapid degradation as they are released from regulatory proteins or smaller RNAs. In Figure 3, the proteins GADPH, Cyclin D, VEGF, and ODC are shown with their predicted free energy. There are studied examples of thermodynamically stable mRNAs that are not translated until allowed to by upstream activators. Their stability may accounted for by post-translational modificatins and sequence elements. The mTOR pathway in eukaryotes, which controls anabolism (growth) and catabolism (use stored energy) based on energy and nutrient availability. The mTOR pathway controls the translation of an mRNA that is stable in the cytoplasm. The downstream mRNA has a 5 prime terminal oligo-pyrimidine tracts modification (TOPS-mRNAs), which confers a more stable mRNA structure in the cytoplasm, than would be predicted by its nucleotide sequence. See figure 3. References: